The identification of new targets for therapeutic intervention is a major hurdle in the development of novel anti-inflammatory therapies. Fortunately, the identification of intracellular receptor proteins of biologically active natural products is yielding new targets for drug development. Recently, one promising anti-inflammatory, immunosuppressive and anti-tumor diterpene triepoxide containing natural product, triptolide, from the Chinese medicine herb Tripterygium wilfordii Hook F, has been shown to block NF-kappaB-mediated transcription. Interestingly, unlike the vast majority of anti-inflammatory agents, triptolide does not inhibit NFkappaB nuclear translocation or DNA binding but rather inhibits its transcriptional activating ability. The mechanism for this unique mode of NF-kappaB inhibition remains unknown. Taking a multi-disciplinary approach, we propose to explore the molecular mechanisms of triptolide's antiinflammatory and anti-proliferative activity through the purification and characterization of triptolide-binding proteins. A careful biological/biochemical validation of these triptolide binding activities will greatly aid our understanding of triptolide's potent anti-inflammatory effects and in the basic biology of NF-kappaB transcriptional activation. In addition, this information and that gained from the further exploration of the triptolide-sensitive inflammatory signaling pathway(s) may provide the basis for the development of novel anti-inflammatory, immunosuppressive and anti-proliferative drugs.